REVIEWpublished: 24 February 2021

doi: 10.3389/fneur.2021.638132

Frontiers in Neurology | www.frontiersin.org 1 February 2021 | Volume 12 | Article 638132

Edited by:

Jian Hai,

Tongji Hospital Affiliated to Tongji

University, China

Reviewed by:

Marek Czosnyka,

University of Cambridge,

United Kingdom

Danilo Cardim,

University of Texas Southwestern

Medical Center, United States

*Correspondence:

Teodor M. Svedung Wettervik

teodor.svedung-wettervik@

neuro.uu.se

Specialty section:

This article was submitted to

Neurotrauma,

a section of the journal

Frontiers in Neurology

Received: 05 December 2020

Accepted: 20 January 2021

Published: 24 February 2021

Citation:

Svedung Wettervik TM, Lewén A and

Enblad P (2021) Fine Tuning of

Traumatic Brain Injury Management in

Neurointensive Care—Indicative

Observations and Future

Perspectives.

Front. Neurol. 12:638132.

doi: 10.3389/fneur.2021.638132

Fine Tuning of Traumatic Brain InjuryManagement in NeurointensiveCare—Indicative Observations andFuture PerspectivesTeodor M. Svedung Wettervik*, Anders Lewén and Per Enblad

Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala, Sweden

Neurointensive care (NIC) has contributed to great improvements in clinical outcomes

for patients with severe traumatic brain injury (TBI) by preventing, detecting, and

treating secondary insults and thereby reducing secondary brain injury. Traditional NIC

management has mainly focused on generally applicable escalated treatment protocols

to avoid high intracranial pressure (ICP) and to keep the cerebral perfusion pressure

(CPP) at sufficiently high levels. However, TBI is a very heterogeneous disease regarding

the type of injury, age, comorbidity, secondary injury mechanisms, etc. In recent years,

the introduction of multimodality monitoring, including, e.g., pressure autoregulation,

brain tissue oxygenation, and cerebral energy metabolism, in addition to ICP and CPP,

has increased the understanding of the complex pathophysiology and the physiological

effects of treatments in this condition. In this article, we will present some potential future

approaches for more individualized patient management and fine-tuning of NIC, taking

advantage of multimodal monitoring to further improve outcome after severe TBI.

Keywords: multimodality monitoring, secondary brain injury, secondary insults, neurointensive care, traumatic

brain injury

INTRODUCTION

In the later decades of the twentieth century, the understanding of the critical factors responsiblefor neurological deterioration after traumatic brain injury (TBI) increased (1). It became clear thatalthough the primary brain injury after TBI cannot be cured, secondary insults leading to furtherbrain injury can be avoided by vigilant monitoring with attentive prevention and early treatmentof such insults. This led to the development of standardized management protocols for severe TBIat specialized neurointensive care (NIC) units, resulting in significant improvements in the clinicaloutcome for these patients (2, 3).

The concept of NIC, to avoid secondary brain injury by intensive monitoring and aggressivetreatment of emerging secondary insults, is still the fundamental basis for modern NIC. Thepurpose of this presentation was to give an overview of potential directions toward the NIC ofthe future. The structure of this review is based on the critical steps to achieve sufficient cerebralenergy metabolism for neuronal survival in relation to multimodality monitoring (Figure 1).

Svedung Wettervik et al. NIC in TBI—Future Directions

TRADITIONAL TREATMENT TARGETS INNEUROINTENSIVE CARE

Intracranial Pressure—Step 1In the early NIC, the main focus was to avoid high intracranialpressure (ICP). The basic understanding of ICP dynamicswas derived from the Monro–Kellie hypothesis, indicating thatICP will increase due to the progression of posttraumaticintracranial hemorrhages or brain edema when there is nomore compensatory reserve to reduce any other intracranialvolume (4). Severe intracranial hypertension leads to brainherniation syndromes, cerebral hypoperfusion, and, ultimately,fatal outcome if untreated. In awake TBI patients, progressingintracranial hypertension may be detected by clinical evaluationas neurological deterioration, but it may be much more difficultto detect this in time in already comatose patients who areintubated and sedated.

Invasive ICP monitoring was introduced in the 1950s byGuillaume (5), further developed in the 1960s by Lundberg(6), and has ever since been used in NIC (Tables 1, 2,Figure 1). Over the years, the definition of what ICP thresholddichotomizes acceptable and dangerous ICP elevation hasbeen extensively debated (7, 13, 14), and the value of ICPmonitoring has also been questioned (15). However, the currentBrain Trauma Foundation (BTF) guidelines recommend ICP

FIGURE 1 | Five critical steps in the pathway to cerebral energy metabolism in relation to multimodality monitoring. By monitoring all the steps in this pathway to

achieve sufficient cerebral energy metabolism, energy failure may be detected in time and the correct diagnosis can be made. Treatments should aim at counteracting

the specific mechanism that causes cerebral energy metabolic disturbances.

monitoring in unconscious TBI patients and suggest an upperthreshold at 22 mmHg (7). In the case of higher ICP,lowering therapies such as evacuation of significant intracranialhematomas, mild hyperventilation, cerebrospinal fluid (CSF)drainage, barbiturates, and decompressive craniectomy may beused in tiered protocols (7, 16, 17).

Cerebral Perfusion Pressure—Step 2Cerebral perfusion pressure (CPP), defined as the pressuregradient between the mean arterial blood pressure (MAP)and ICP, is another important treatment target in TBI duringNIC (Tables 1, 2, Figure 1). CPP is considered a surrogatemeasure for global cerebral blood flow (CBF). Early studiesstressed the importance of keeping CPP at high levels above70 mmHg (18) to avoid cerebral ischemia and counteract thevasodilatory cascade. However, the Lund concept suggested thatCPP values as low as 50 mmHg can usually be tolerated, whereasvalues above 70 mmHg may induce brain edema (8). Today,the current guidelines recommend a CPP between 60 and 70mmHg as a balance between the risk of cerebral hypo- andhyperperfusion (7).

Systemic Monitoring VariablesIn traditional NIC of TBI, ICP and CPP have been the two maintreatment targets, but other variables have also been considered,

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TABLE 1 | Multimodality monitoring—a selection of methods and their benefits and limitations.

Physiological

variable

Monitoring method Continuous/Intermittent Global/Focal Benefits Limitations

ICP EVD Continuous Global Both monitoring and

treatment of ICP by CSF

drainage.

Infection risk. Impossible

when compressed ventricles.

Risk of invalid ICP monitoring

in case of slit ventricle.

Intraparenchymal sensor Continuous Global Possible also when

compressed ventricles.

Invalid ICP monitoring due

to slit ventricle is not a

problem.

Does not offer ICP treatment

with CSF drainage.

CPP ICP device and arterial line

for continuous systemic

ABP.

Continuous Global Feasible, continuous

global CBF surrogate.

Unreliable surrogate, does

not consider cerebrovascular

resistance.

CBF autoregulation PRx (ICP and ABP) Continuous with time

window

Global Feasible measure of the

global autoregulatory

status.

Low signal-to-noise ratio.

Does not take into account

focal asymmetries.

CPPopt (PRx and CPP) Continuous with time

window

Global Feasible, continuous

global CBF surrogate.

Frequent absence of

U-shaped curves. Does not

take into account focal

asymmetries. Requires

advanced software.

Mx (TCD and CPP) Intermittent Global and focal May detect regional

autoregulatory differences.

User-dependent. Poor

evaluation of the posterior

circulation.

Cerebral blood flow Radiology (Xe-CT, PET,

MRI)

Intermittent Global and focal Both global and focal. Difficult to transport unstable

patients to the radiology

department.

TCD Intermittent Global and focal Feasible and may be used

bedside.

Measures velocity.

User-dependent. Poor

evaluation of the posterior

circulation.

Intraparenchymal thermal

diffusion probe

Continuous Focal Feasible and continuous

CBF measure.

Unreliable. Focal, does not

take into account variabilty in

CBF between brain regions.

Brain tissue

oxygenation

Jugular bulb catheter

(SjvO2)

Continuous Global Continuous and feasible

global measure.

Low sensitivity for focal

ischemia.

Intraparenchymal device

(BtO2)

Continuous Focal Continuous and feasible

focal measure.

Variabilty in oxygenation

between brain regions.

NIRS Continuous Focal Non-invasive. Unreliable. Does not evaluate

the posterior circulation.

Cerebral energy

metabolism

MD Continuous Focal Feasible for continuous

evaluation.

Variability in energy

metabolism between brain

regions.

PET Intermittent Global and focal Possible to investigate

complex aspects of

energy metabolism.

Difficult to transport unstable

patients to the radiology

department.

ABP, Arterial blood pressure; CBF, Cerebral blood flow; CSF, Cerebrospinal fluid; EVD, external ventricular drain; ICP, Intracranial pressure; MD, Microdialysis; Mx, Mean flow inex; NIRS,

Near infrared spectroscopy; PET, Positron emission tomography; PRx, Pressure reactivity index; TCD, Transcranial Doppler; Xe-CT, Xenon-enhanced computed tomography.

e.g., to maintain sufficient arterial oxygenation (pO2 ≥ 12kPa), to avoid systemic hyperthermia (T < 38◦C), and to keeparterial glucose within normal limits (5–10mM) (2, 19). Figure 2demonstrates the Uppsala standardized TBI managementprotocol as an example of a local escalated ICP-orientedmanagement protocol with a focus on avoiding secondary insults(2, 11, 19).

INDICATIVE OBSERVATIONS AND FUTUREPERSPECTIVES

Multimodality Monitoring of the ComplexPathophysiology in Traumatic Brain InjuryThe traditional NIC treatment targets in TBI, ICP, and CPP, aretwo important surrogate measures of the cerebral environment,

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Svedung Wettervik et al. NIC in TBI—Future Directions

TABLE 2 | Monitoring variables, target intervals, and treatments.

Variable Target interval Treatment

ICP BTF: ICP ≤ 22mm Hg (7)

Uppsala: ICP ≤ 20mm Hg (2)

Head elevation

Hematoma evacuation

Hyperventilation

CSF drainage

Sedation

Barbiturates

Decompressive craniectomy

CPP BTF: 60 to 70mm Hg (7)

Uppsala: CPP ≥ 60mm Hg

(2)

Lund concept: CPP 50 to

70mm Hg (8)

Autoregulatory management:

CPP close to CPPopt (9)

ICP control (above)

Intravenous fluids

Vasopressors

CBF pressure

autoregulation

BTF: No target (7)

Uppsala: No target (2)

CPP optimum

Hyperventilation

Hyperoxia

Body temperature control

Arterial glucose and

lactate management

CBF BTF: No target (7)

Uppsala: No target (2)

CPP and

autoregulationmanagement

Arterial

oxygenation

BTF: No target (7)

Uppsala: pO2 > 12 kPa and

Hgb > 100 g/L (2)

Respiratory optimization

Red blood cell traunsfusion

Arterial

glucose

BTF: No target (7)

Uppsala: 5–10mM (2)

Tight glycemic control:

4.4–6.1mM (10)

Intravenous glucose

Insulin injection/infusion

Cerebral

oxygenation

BTF: No target (7)

Uppsala: No target (2)

CBF and arterial

oxygenation management

Cerebral

glucose

BTF: No target (7)

Uppsala: No target, but

clinical evaluation if cerebral

glucose < 0.5mM (MD) (11)

MD consensus meeting 2014:

Cerebral glucose >

0.2–0.8mM (12)

CBF and arterial

glucose management

Cerebral

energy

metabolism

BTF: No target (7)

Uppsala: No target, but

clinical evaluation if cerebral

LPR > 40 (MD) (11)

MD consensus meeting 2014:

Cerebral LPR < 25–40 (12)

Optimize the

variables above.

BTF, Brain Trauma Foundation; CBF, Cerebral blood flow; CPP, Cerebral perfusion

pressure; CPPopt, Optimal CPP; CSF, Cerebrospinal fluid; ICP, Intracranial pressure; LPR,

Lactate-/pyruvate ratio; MD, Microdialysis.

but many other variables are also crucial steps in the pathwayto achieve an optimal cerebral energy metabolic state (Figure 1).CBF delivers oxygen and glucose to the injured brain. Theautoregulation of CBF by the cerebral vessels is often disturbedafter TBI and focal CBF disturbances may occur despitenormal ICP and CPP (20–24). In addition, systemic traumaticinjuries could precipitate for arterial hypoxia with secondarybrain tissue hypoxia despite normal CBF in the large cerebralvessels. Furthermore, microvascular thrombosis and diffusionlimitations from brain edema may limit oxygen delivery in

the microvascular circulation despite normal macrovascularCBF and arterial oxygenation (25, 26). However, even if braintissue oxygenation and the level of energy metabolites are atadequate levels, cerebral energy failure may still occur due tomitochondrial dysfunction (26–28). In addition, mechanismssuch as seizures and hyperthermia increase energy consumptionand may be detrimental if the compensatory cerebral energyreserve is compromised (29–33).

Multimodality monitoring makes it possible to continuouslysurveil the different steps in the pathway to cerebral energymetabolism (Tables 1, 2 and Figure 1). The methods used areboth global and focal, as well as continuous and intermittent.Some methods give direct information about the crucialparameters for the energy metabolism and others provideindirect measures. The complete picture is obtained by anintegrated analysis of all measures. The future direction of NICis a more detailed analysis of each of the crucial pathwaysfor cerebral energy metabolism using multimodality monitoringin order to identify the correct cause of energy metabolicdisturbances (Table 3) (34). This may in turn lead to a moretimely and cause-specific treatment. The following sectionswill review the background and potential future applicationsof some monitoring techniques for the fine-tuning of next-generation NIC.

CBF Pressure Autoregulation and CPPManagement—Step 2Global and regional CBF can be measured intermittently withdifferent imaging techniques, and regional CBF can also bemeasured continuously by means of an intraparenchymal probe(Table 1). It would be advantageous to continuously monitorglobal CBF, but there is, at present, no feasible way. CPP iscurrently the best surrogate measure for global CBF, but thisconcept leaves the cerebrovascular reactivity out of the equation,and there is an interest to find better surrogate measures of CBFthat takes both CPP and the cerebrovascular status into account.

Lassen described the cerebral autoregulation in 1959 ashe demonstrated that CBF is maintained over a wide rangeof MAPs (35, 36). The autoregulatory capacity may becomederanged following TBI, which is strongly associated with pooroutcome (14, 21, 37). Several methods to monitor the cerebralautoregulation in the NIC have been introduced (Table 1),such as the mean flow index (Mx) and the pressure reactivityindex (PRx). PRx has received the greatest interest and iscontinuously measured as the correlation coefficient betweenMAP and ICP over 5min (37). Negative index values indicateintact pressure autoregulation, such as when an increase inMAP leads to cerebral vasoconstriction to maintain normalCBF with a corresponding reduction in CBV and ICP. Positiveindex values indicate disturbed pressure autoregulation, such aswhen an increase in MAP leads to passive cerebral vasodilationwith corresponding increases in CBF, CBV, and ICP (37–39).The clinical utility of PRx is still under development. However,as low PRx values are associated with better clinical outcome,autoregulatory-oriented management that aims at improvingPRx has been suggested, as outlined below.

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FIGURE 2 | The Uppsala standardized traumatic brain injury (TBI) management protocol as an example of a local escalated intracranial pressure (ICP)-oriented

management protocol with a focus on avoiding secondary insults. The figure demonstrates an example of a local ICP-oriented management protocol (2). The

therapeutic intensity is gradually increased by starting with ICP-lowering treatments that carry a lower risk of complications and escalating to treatments with greater

risks if the ICP target cannot otherwise be controlled. Decompressive craniectomy may be performed both on a primary indication (first surgical procedure, i.e., the

fourth step is used as the first step) in the case of severe brain edema in the early course, but chiefly on a secondary indication (when all other treatments are

exhausted).

Autoregulatory management aims at giving the patienttreatments that improve the autoregulatory capacity. Particularly,the association between pressure autoregulation and CPP hasreceived interest. In a first attempt to consider autoregulationin CPP management, patients were classified as either pressureactive or pressure passive, and the absolute autoregulatory statuswas suggested to determine whether the patient would benefitfrom high or low CPP (40). It was then demonstrated in anobservational study including two centers with different CPPphilosophy (Uppsala and Edinburgh) that patients with pressure-passive cerebral vessels (high PRx) had better outcomes if treatedwith ICP-oriented therapy with relatively lower CPP targets,whereas pressure-active patients (low PRx) benefitted from CPP-oriented treatment with relatively higher CPP targets (41). Inthe next attempt, it was found that PRx varies with CPP in aU-shaped way and that the CPP with the concurrently lowestPRx could be targeted where autoregulation works best (22),as demonstrated in Figure 3. Several studies have supportedthat deviation of the absolute CPP above and below theoptimal (CPPopt) is associated with poor outcomes (24, 42–45).Furthermore, brain tissue oxygenation reaches a plateau whenCPP approaches CPPopt, indicating optimal CBF (46). These

findings support that CPPopt may be a better CBF surrogate thattakes into account both the absolute CPP and the cerebrovascularstatus for the individual patient.

However, despite these promising findings, several concernshave been raised regarding CPPopt that need to be addressedin future trials. The U-shaped association between CPP andPRx is absent during ∼40% of the monitoring time (47), whichlimits the feasibility of CPPopt as a target (48). Secondly, theappearance of the U-shaped curvemay vary from flat to steep andthe absolute PRx at CPPopt may vary from negative to positivevalues (Figure 3). The necessity to keeping CPP close to CPPoptprobably depends on the curve shape and the absolute PRx (42).For example, if CPPopt is high, the absolute PRx is negative, andthe U-shaped curve is relatively flat, the Lassen plateau phaseof autoregulation should be acceptably wide and a much lowerabsolute CPP below CPPopt could then be allowed since highertargets are otherwise associated with complications such as acuterespiratory distress syndrome (49). On the contrary, it could bemore critical to keep CPP close to CPPopt if the curve is steepand PRx is high. Thirdly, although patients that spontaneouslyhad CPP values close to CPPopt had better clinical outcomein retrospective studies (43), CPPopt as an active treatment

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target has so far not been sufficiently investigated prospectively(50). Particularly, CPPopt is often above 70 mmHg, i.e., abovethe upper fixed threshold according to the BTF guidelines (7),but using vasopressors to achieve such high targets could carryadverse effects. The safety and feasibility of CPPopt as a treatmenttarget is investigated in a multicenter randomized controlled trial(COGiTATE) (9). The results of this trial will determine thefuture directions of CPP research and management in TBI care.

TABLE 3 | Secondary brain injury conditions, multimodality monitoring patterns

and potential cause-specific treatments.

Condition Multimodality monitoring

pattern

Potential treatments

Intracranial

hypertension

High ICP, low CPP, brain tissue

hypoxia, and high LPR

ICP lowering treatments

Arterial

hypotension

Normal ICP, low ABP/CPP, brain

tissue hypoxia, and high LPR.

Address cause for arterial

hypotension, give

intravenous fluids and

vasopressors. Arterial

hyperoxia treatment?

Autoregulatory

disturbances

Normal to high ICP, low to high

CPP, high PRx, brain tissue

hypoxia, and high LPR.

Target CPPopt, treat high

ICP, keep arterial glucose,

pO2 and pCO2 within

optimal intervals.

Oxygen diffusion

limitation

Normal ICP, normal CPP, brain

tissue hypoxia, and high LPR.

Arterial hyperoxia

treatment.

Cerebral

hypermetabolism

Normal ICP, normal CPP, possibly

brain tissue hypoxia, low cerebral

glucose and pyruvate, and high

LPR.

Body temperature and

seizure control. Sedation.

Arterial hyperoxia

treatment?

Mitochondrial

dysfunction

Normal ICP, normal CPP, normal

brain tissue oxygenation, normal

cerebral glucose and pyruvate,

and high LPR.

Arterial hyperoxia?

Cyclosporin A?

The table illustrates different multimodality monitoring patterns for different clinical

conditions, including e.g., cerebral ischemia with delivery failure of cerebral energy

metabolites, as well as when the cerebral energy metabolic state is compromised due

to hypermetabolism or poor mitochondrial function.

Autoregulatory Management and SystemicPhysiology—Step 2In addition to CPP, several other variables that controlthe cerebrovascular resistance are associated with pressureautoregulation and could potentially be targeted in an integratedautoregulatory protocol. Arterial hyperglycemia may disturbthe endothelial and myogenic function of the cerebral vessels(51, 52). In line with these findings, we and others havedemonstrated that arterial hyperglycemia is independentlyassociated with a higher PRx (53, 54), indicating that a tighterglycemic control at least below 10mM could be beneficialfrom an autoregulatory point of view. Furthermore, lactateis a cerebral vasodilator and higher systemic levels mayincrease CBF (55). However, we have found that a higherarterial lactate is independently associated with a higher PRx(33), and it is possible that the corresponding increase inCBF (55) represents dysregulated hyperemia. This calls forcaution in clinical TBI trials on lactate-based fluids as a wayof increasing the delivery of an alternative energy fuel tothe brain due to the possible negative effect of lactate onpressure autoregulation. Hyperthermia could induce cerebralvasodilation, and some findings support an association betweena higher body temperature and a higher PRx (56), whereasother studies have found no such association (33). Arterialhypoxia also leads to cerebral vasodilation in order to increaseCBF to maintain normal brain tissue oxygenation (57), whereashigher oxygen levels may increase the cerebrovascular tone.We have found that higher arterial oxygen levels above12 kPa are associated with lower PRx, i.e., better pressureautoregulation (58). Similarly, increased cerebrovascular tone byhyperventilation is associated with better pressure autoregulation(56, 59, 60).

Hence, several systemic variables, in addition to CPP,could potentially be targeted in an integrated autoregulatoryprotocol including, e.g., temperature management,glycemic control, and respiratory targets to optimize pO2

and pCO2.

FIGURE 3 | Optimal cerebral perfusion pressure (CPPopt)—differences in curve shape. The CPPopt curves may vary over time and between patients, as illustrated in

these three different curves. There are questions on how the curve shape and the absolute pressure reactivity index (PRx) are relevant in CPPopt management.

Patients with a steeper CPPopt curve may, in theory, be more vulnerable to changes in CPP.

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Arterial and Brain Oxygenation—Steps 3and 4Ischemic and hypoxic secondary brain injuries are common afterTBI (61), and treatment aims at maintaining adequate CBF andarterial oxygen content for aerobic energy metabolism. Arterialoxygen content is monitored with repeated arterial blood gasanalyses of hemoglobin (Hgb) and pO2 and continuously withpulse oximetry (SpO2). The arterial oxygen content is, to a greatextent, dependent on the level of oxygen-binding Hgb, whereasdissolved oxygen only constitutes a fraction of the total arterialoxygen content under normal conditions (62). There is greatcontroversy regarding the definition of clinically relevant anemiafor cerebral oxygen delivery, but an Hgb below 9 g/dl maydiscriminate when the risk of cerebral hypoxia is significantlyincreased (63). Although red blood cell transfusion (RBCT) couldimprove cerebral oxygen delivery (64), adverse effects such asa worsening in pressure autoregulation (65) and an increasedrisk of thromboembolic events have been described (66). Clinicalstudies on liberal vs. restricted RBCT based on Hgb thresholds(e.g., 10 vs. 7 g/dl) indicate a neutral to negative effect on clinicaloutcomes with the liberal approach (64, 66–69). The observationsthat both anemia and RBCT are independently associated withpoor outcomes make the clinical management difficult, but it ispossible that the indication for RBCT could be guided by meansof multimodal monitoring. Despite, or because, the controversyin this matter, there is currently no BTF guidelines on RBCT insevere TBI (7).

There is also limited knowledge and lack of guidelinesregarding specific arterial oxygen thresholds (7), but pO2

levels above 12 kPa and SaO2 above 95% may be targeted(2). Additionally, brain tissue oxygenation can be monitoredglobally with a jugular vein bulb (SjvO2) and focally withan intraparenchymal probe (BtO2) (Table 1). BTF currentlyrecommends SjvO2 monitoring and avoiding ischemic SjvO2

levels below 50% (7). There is no BTF recommendation on BtO2

monitoring (7), but focal brain tissue hypoxia below 20 mmHghas been associated with poor clinical outcomes (70).

Although there is only a small fraction of free and dissolvedpO2 in the blood (62), an increase in pO2 to hyperoxic levelscould still be beneficial in TBI. Increasing the fraction of theinspired oxygen (FiO2), i.e., normobaric hyperoxia (NBO), hasbeen proven to increase arterial and brain tissue oxygenation(71). NBOmay then compensate for ischemic hypoxia, overcomediffusion barriers, and improve mitochondrial function (62).Hyperoxia reduces cerebral glycolytic enzymes and therebydecreases pyruvate and lactate (57, 71, 72), but there are questionswhether cerebral oxidative energy metabolism improves. A PETstudy found that hyperoxia improves energy metabolism inischemic brain regions (73), and microdialysis (MD) studiessupport true energy metabolic improvements in the case ofpoor substrate supply (58) or anaerobic energy metabolism (74).On the other end, some studies suggest that hyperoxia inducesdetrimental reactive oxygen species that negatively affect cerebraltissue survival, although this may only occur to a small extentin a limited number of patients (75). Brain tissue oxygen-guidedtreatment protocols have been introduced, in which low brain

tissue oxygenation may be treated with an increase in FiO2.However, there is still clinical equipoise of this approach dueto small positive to neutral effects on clinical outcomes inprospective trials (76–78).

Delivery of Cerebral Energy Metabolites,Cerebral Energy Metabolism,Neurochemical Monitoring, andTreatments—Steps 3, 4, and 5Cerebral nutrients, such as glucose and lactate, are delivered bythe CBF. The arterial levels may be monitored with repeatedarterial blood gases to ensure sufficient arterial content. Thecerebral energy metabolites, glucose, pyruvate, and lactate, aswell as the rate of oxidative energy metabolism (lactate/pyruvateratio, LPR) may be evaluated with hourly measures by meansof cerebral MD, i.e., a double-lumen, semi-permeable catheterthat is perfused with artificial CSF (79, 80). The catheter caneither be placed in macroscopically normal-appearing braintissue to estimate global cerebral energy metabolism or in peri-contusional areas to estimate focal cerebral energy metabolismin “tissue-at-risk” (81). Recently, the new MD system (Loke)has been introduced, which measures cerebral glucose, pyruvate,and lactate minute by minute. This may reveal the complexexplanatory variables for cerebral energy metabolism in higherresolution. The cerebral energymetabolismmay also be evaluatedwith radiological snapshots using PET (Table 1).

Glucose is the main cerebral energy fuel. The arterial glucoselevel and CBF determine cerebral glucose delivery, but thecerebral glucose level also depends on the cerebral energymetabolic rate. Arterial and cerebral glucose are normallycorrelated, but this association may be disturbed after TBI(33, 54, 82–84) as the CBF and cerebral energy metabolic ratecould have greater influence on cerebral glucose levels. Theimmediate effects of TBI include a sympathetic stress responsethat, among other things, gives rise to a surge in arterial glucose(85). This is beneficial since it is necessary to avoid arterialhypoglycemia and neuroglycopenia for the vulnerable brain, butarterial hyperglycemia is also associated with worse outcomesafter TBI (86–88). Although the latter association could reflectmore severe underlying traumatic injuries, hyperglycemia could,per se, induce secondary brain injury by causing disturbancesin cerebral autoregulation and mitochondrial function (54, 89).Since both too low and too high arterial glucose could exert anegative effect on the brain, tight glycemic control with intensiveinsulin therapy (IIT) management has been suggested in TBIcare. IIT showed promising results in general ICU patients at anearly stage (10, 90, 91), but recent studies show that IIT causesan increased burden of arterial hypoglycemia that outweighsthe benefits of avoiding hyperglycemia, resulting in a neutral tonegative net effect on outcomes in various ICU populations aswell as in TBI (92–97). Specifically, TBI patients treated withIIT developed more severe energy metabolic disturbances withreductions in cerebral glucose and oxidative energy metabolismthan those treated with conventional glycemic control (95, 98).Hence, a narrow arterial glucose interval is appealing in theory,

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but is currently not feasible due to the risk of overtreatment. BTFdoes not have any recommendation on optimal glucose levelsor management in TBI (7). Due to the lack of clear evidenceof benefits for IIT in the NIC setting, a looser glycemic controlis mostly applied, e.g., between 5 and 10mM (99). CerebralMD glucose below 0.2–0.8mM is considered dangerously low,and such thresholds could aid in guiding treatment for whenthe termination of insulin treatment or infusion of glucose iswarranted (12).

The understanding of arterial lactate as an additional cerebralenergy substrate (100) has increased in the last years. However,the arterial contribution to cerebral lactate is only 10% whenthe arterial lactate concentration is 1mM, but increases to60% at 5mM (101). An increased consumption of lactateas an energy fuel may, in turn, spare cerebral glucose (55,102, 103). Higher lactate decreases the cerebrovascular tone,induces vasodilation, and increases CBF (55, 104), but possiblyat the expense of a worsened pressure autoregulation (33).Exogenous, hypertonic lactate may exert anti-edematous effectsand alleviate intracranial hypertension (102). Animal TBI studiessupport a reduction in lesion volume after exogenous lactateinfusion (105). Clinical trials also indicate that exogenous lactateimproves outcomes (106), although a higher endogenous arteriallactate is independently associated with worse outcomes afterTBI (33). Future studies are needed to determine the roleof intravenous lactate supplement in TBI care. Nevertheless,high endogenous levels of cerebral lactate above 4mM indicateanaerobic energymetabolism and are associated with unfavorableclinical outcomes (12, 107).

Furthermore, high cerebral MD LPRs above 25–40 indicatedisturbed cerebral energy metabolism (12, 107). The etiologyfor LPR elevations may differ. A high LPR with concurrentlylow cerebral glucose and pyruvate has been suggested to reflectcerebral ischemia/substrate delivery failure, whereas a high LPRwith concurrently normal/high cerebral glucose and pyruvatehas been suggested to reflect mitochondrial dysfunction (26).Substrate delivery could, in theory, be improved by a higherCPP, improved pressure autoregulation, and higher arterialsubstrate content (Table 3). The importance of mitochondrialdysfunction has gained increased interest and understanding inrecent years. There is currently no treatment for this condition,but cyclosporine A, which is an immunosuppressant, improvesthe mitochondrial function in animal TBI models and hasdemonstrated some promise in preliminary human trials, butlarger studies are needed to evaluate its efficacy (108, 109).

MD may also aid in monitoring more complex dynamicpathophysiological processes in the brain following TBI.Neuroinflammation after TBI may exert both beneficial andnegative effects on the brain, depending on the time windowafter injury and the specific mechanisms (110). MD can beused to evaluate neuroinflammatory biomarkers bedside in orderto better understand the neuroinflammatory mechanisms, theirrelation to the dynamic clinical course, secondary insults, andclinical outcomes in TBI (111, 112). This may aid in thedevelopment of optimal neuroprotective agents, as outlinedbelow, and the cerebral MD biomarkers could potentially be usedto improve the indication for such treatments.

Neuroprotective AgentsIn addition to the secondary physiological insults, there is acascade of injurymechanisms on the cellular andmolecular levelsafter the primary brain injury, e.g., toxic release of excitatoryneurotransmitters, apoptotic pathways, neuroinflammation, andmitochondrial dysfunction (113). Many neuroprotective agentshave been developed to counteract these pathomechanisms,but there has so far been limited success in translation fromanimal to clinical studies (113). For example, N-methyl-D-aspartate (NMDA) receptor antagonists and calcium channelantagonists both reduce excitotoxicity in animal TBI models,but their efficacy in human TBI trials has been limited (114,115). Human TBI trials on immunomodulating agents have alsobeen disappointing. Progesterone had a neutral effect (116),whereas corticosteroids even worsened clinical outcomes (117).As outlined above, cyclosporine A has demonstrated somepromise in preliminary human trials, but larger studies areneeded to evaluate its efficacy (108, 109).

One reason for the so far disappointing results ofneuroprotective drugs in humans may be that the therapeutictime window is limited, and it may be difficult to administerthe treatments within the right time in the clinical setting.Furthermore, TBI in humans is very heterogeneous, and thesubtype may be of importance for the therapeutic effect. Animaltrials are often based on relatively homogenous TBI models,while the clinical trials often have included all types of TBIpatients. Many pharmacological trials have also been donein the dawn of NIC, when secondary insults were not yet asefficiently surveyed and managed as today, and the relativeimportance of these agents might have been less significantin that setting. In conclusion, despite the limited effect of theneuroprotective agents shown in human TBI trials, it is possiblethat neuroprotective agents with a more optimal treatmenttiming, better understanding of the injury processes, and animproved patient selection in a high-quality NIC setting couldyield improved outcomes. Future studies that take these aspectsinto account are needed.

Multimodality Monitoring and PrecisionMedicineThemultimodality monitoring patternmay reveal the underlyingetiology of cerebral energy failure following TBI so that cause-specific treatments may be initiated (Table 3). For example, incases of intracranial hypertension, low CPP, brain tissue hypoxia,and cerebral energy failure, treatments should aim at loweringICP to improve the cerebral environment. In other cases withnormal ICP, CPP within optimal targets, and normal arterialoxygenation, but poor brain tissue oxygenation and concurrentcerebral energy metabolic failure (Figure 4), arterial hyperoxiacould be used to possibly overcome cerebral diffusion barriers.In cases where all variables such as ICP, CPP, and brain tissueoxygenation are within the targeted intervals, except for theenergy metabolic state (LPR), mitochondrial dysfunction is aplausible explanation. There is currently no treatment for thiscondition, but there are ongoing trials for, e.g., neuroprotectiveagents that may relieve mitochondrial dysfunction.

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Svedung Wettervik et al. NIC in TBI—Future Directions

FIGURE 4 | Illustrative patient case with multimodal monitoring. The figure demonstrates the temporal evolution of cerebral physiology over ∼2 days. Although

intracranial pressure (ICP), cerebral perfusion pressure (CPP), pressure reactivity index (PRx), and oxygen saturation (SpO2) were within adequate intervals, the patient

developed brain tissue hypoxia and cerebral energy failure (high lactate/pyruvate ratio). The pathophysiology may include microvascular thrombosis and/or increased

diffusion limitations from cerebral edema.

Cerebral Monitoring in a Resource-LimitedSettingHigh-resolution multimodal monitoring offers the best methodto fully evaluate the cerebral environment after TBI, but suchtools may be limited to a few research-minded academic centers.There is, hence, also an interest inmore feasible monitoring tools.PRx and CPPopt both require high-resolution data and advancedsoftware. However, low-frequency autoregulation index (LAx)and the corresponding LAx-derived CPPopt are based onminute-by-minute data, require less advance software, and maybe a fair substitute for centers without access to PRx andCPPopt (118). Transcranial Doppler is also a feasible noninvasiveand accessible method to assess cerebral blood flow velocity,particularly in the absence of CPP and advanced radiologicalimaging, and could be used to guide blood pressure management.

CONCLUDING REMARKS

Traditional NIC has focused on reducing secondary braininjury by treating elevated ICP and maintaining the CPPsufficiently high to avoid cerebral ischemia. However, recentfindings support that the TBI pathophysiology is muchmore complex and cerebral energy failure frequently occursin the absence of intracranial hypertension and low CPP.

Particularly, the roles of pathomechanisms such as disturbancesin pressure autoregulation, microvascular thrombosis, oxygendiffusion limitations, and mitochondrial dysfunction have gainedincreased understanding. By multimodal monitoring, cerebralenergy metabolic failure may be detected earlier and its etiologycould be better diagnosed. This may, in turn, lead to precisionmedicine with more cause-specific treatments to avoid secondarybrain injury for these patients. Future studies are needed toelaborate on the strengths and limitations of certain monitoringtools and their role in guiding cause-specific treatments in NICof severe TBI.

AUTHOR CONTRIBUTIONS

TS: conceptualization, writing–original draft. AL:conceptualization, writing–review and editing. PE:conceptualization, supervision, writing–review and editing.All authors contributed to the article and approved thesubmitted version.

FUNDING

The research was supported by the Department ofNeuroscience/Neurosurgery, Uppsala University, Sweden.

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Conflict of Interest: The authors declare that the research was conducted in the

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